Summary: Prostate cancer (PCa) that initially develops in the prostate gland is curable by surgery and radiotherapy. The standard choice of treatment for PCa is by androgen ablation since PCa cells survive on the availability of androgen hormone. Although this treatment approach is effective initially, PCa recur invariably and do not respond to hormonal therapy. However when the cancer has spread to other parts of the body and such form of recurrent cancer known as metastatic castration-resistant prostate cancer (CRPC) is practically incurable and lethal. Hence, there is an urgent need to develop effective and safe anti-cancer alternatives such as compounds derived from diet to successfully control CRPC. Piperine (PIP), a natural alkaloid abundantly present in pepper spice has several pharmacological benefits including anti-cancer activity. Our recent publication for the first time showed that PIP inhibits both hormone-dependent and hormone-independent prostate tumor growth in nude mice model. Importantly, we showed that PIP down regulates the expression of androgen receptor (AR) resulting in the reduction of PSA levels in PCa cells. However, whether PIP has anti-metastatic properties in CRPC cells are not known. Our subsequent preliminary studies identified that PIP targets the transcription of Translationally Controlled Tumor Protein (TCTP), an anti-apoptotic protein that promotes the metastatic properties of CRPC cells. Downregulation of TCTP by PIP also results in the activation of E-cadherin, a tumor suppressor molecule in CRPC cells by modulating the expression of key epithelial to mesenchymal transition (EMT) markers such as snail-1 and N-cadherin. Based on these observations, our hypothesis is that dietary administration of PIP can inhibit metastasis development by targeting AR, TCTP and reversing EMT signaling in CRPC cells. This hypothesis will be tested in two specific aims. In Aim 1, we will determine whether dietary administration of PIP can inhibit or prevent metastasis of C4-2B RFP and 22Rv1 RFP cells in an experimental intravenous metastasis model of nude mice. In these studies, tumor metastasis will be used as end points. At the end of the study, metastatic lesions and various organs will be collected for histopathology analyses to determine the effects of PIP on metastasis. Expression of TCTP, AR, ?-SMA, fibronectin, snail-1, N-cadherin, vimentin and E-cadherin in the metastatic tissue samples will also be determined by immunohistochemistry. In Aim 2, we will delineate whether PIP disrupts AR and TCTP-mediated EMT signaling to restore E-cadherin as a mechanism to target metastatic CRPC cells in an in vitro model. In this aim, we will use variety of approaches such as gene silencing, gain of function, pharmacological, promoter and molecular based assays to delineate the anti-metastatic mechanisms of PIP. Results obtained upon successful completion of these proposed specific aims will yield valuable information in developing PIP as a potential anti-metastatic agent in successfully controlling CRPC.